Four physician-scientists will share model systems, reagents and methodologies to expand an interactive program for preclinical and clinical studies on the pathogenesis and treatment of systemic lupus erythematosis. Drs. Davidson, Diamond, Porcelli and Putterman are practicing rheumatologists with established research programs focused on aspects of the initiation of autoreactivity and the mechanisms of target organ damage in SLE. Three core facilities will provide essential support in administration, flow cytometry, and protein expression and tetramer production. Dr. Diamond has recently developed a novel approach for the identification and analysis of autoreactive B cells at the single cell level using fluorescent tagged tetramers of a peptide mimetope for DNA. She will use the methodology to determine which B cell subsets give rise to anti-DNA antibodies in patients with SLE. DR. Davidson proposes to examine the role of newly identified costimulatory molecules in the NZB/W F1 model of lupus and in the peptide antigen-induced model of lupus pioneered by Drs. Diamond and Putterman. Using novel reagents for costimulatory blockade, she will ask whether the memory of B cell compartment is critical in the progression of disease and in relapse after therapy in murine models of lupus. Dr. Porcelli is interested in CD1 restricted T cells. Based on novel data on the regulation of potentially autoreactive marginal zone B cells, he proposes to study the involvement of the CD1 system in the NZB/W F1 mouse and in the antigen-induced model of SLE mentioned above. Dr. Putterman is studying tissue damage in lupus, focusing on anti-DNA antibody-mediated kidney disease. He has recently identified a glomerular antigen recognized by a significant fraction of anti-DNA antibodies; he will explore this antigenic specificity to develop a model for glomerular damage. Together these studies new information and new methodologies to address critical aspects of disease initiation and progression, and tissue damage in lupus. The strategy is to apply information obtained from murine studies to studies of the human disease; thus, the program includes several studies in mice and one study addressing the phenotypic analysis of human lupus B cells drawing on methodologies and hypotheses derived from murine studies. The goal is to develop "designer" therapies tailored to particular subsets of patients with particular patterns of disease induction and tissue injury. This effort is based on already existing interactions among the investigators and will be substantially strengthened by the resources provided by the Program Project.